The human genome contains an abundance of interspersed segmental duplications separated by many megabasepairs of unique DNA. Despite the association of these regions with recurrent genetic disease, the underlying mechanism by which this peculiar architecture has evolved and become so prevalent in the human genome is unknown. Using computational genomic methods and large-scale comparative primate genomic sequence data, this proposal will reconstruct the evolutionary history of all segmental duplications. We will test the hypothesis that certain unstable segments have recurrently duplicated during primate evolution and that these have catalyzed the formation of larger more complex patterns of duplication that have emerged in distinct regions of the genome. Further, we hypothesize that these critical segments are associated more frequently with gene innovations that have experienced positive selection. This proposal will correlate structural and functional aspects of segmental duplications. If successful, it will provide a new model to explain the non-random spatial-temporal distribution of segmental duplications in human and great ape euchromatin and will provide fundamental information regarding the birth-death process of genes and gene families.